1. Field of Invention
The current invention relates to methods for magnetic resonance imaging and spectroscopy. More specifically the field relates to methods for the indirect detection of exchangeable solute protons or protons of exchangeable solute-based water molecules through the water signal that can be used for MRI and to the detection of low-concentration solutes, both exogenous (e.g., contrast agents) and endogenous (e.g., cellular constituents).
2. Discussion of Related Art
Although magnetic resonance imaging (MRI) is an established imaging modality, due to inherent limitations in sensitivity, MRI is at great disadvantage to optical and radioactive methods in detecting low concentration of contrast agents. To make matters worse, most of the (super)para-magnetic metals used to enhance relaxation are toxic when not chelated, the only current exception being iron. This limitation of exogenous MRI contrast to relaxation agents was the status quo until 2000, when Ward and Balaban suggested using exchangeable protons for MRI contrast. This suggestion opened up a new range of possible contrast agents and the possibility to turn contrast on and off by using RF saturation. In fact, based on this procedure of chemical exchange saturation transfer (CEST), the new range of contrast agents have been named CEST agents (Ward, K. M., Aletras, A. H. & Balaban, R. S. A new class of contrast agents for MRI based on proton chemical exchange dependent saturation transfer (CEST). J Magn Reson 143, 79-87 (2000); Ward, K. M. & Balaban, R. S. Determination of pH using water protons and chemical exchange dependent saturation transfer (CEST). Magn Reson Med 44, 799-802 (2000)) as well as U.S. Pat. No. 6,963,769. This chemical exchange saturation transfer may enable large sensitivity enhancements, leading to the detection of CEST contrast agents at low concentrations (μM or even lower) while maintaining the ability to see changes on a 110M water signal (Zhou, J. & van Zijl, P. Chemical exchange saturation transfer imaging and spectroscopy. PROGR. IN NMR SPECTR 48, 109-136 (2006); Sherry, A. D. & Woods, M. Chemical exchange saturation transfer contrast agents for magnetic resonance imaging. Annual review of biomedical engineering 10, 391-411 (2008); De Leon-Rodriguez L M, Lubag A J, Malloy C R, Martinez G V, Gillies R J, Sherry A D. Responsive MRI agents for sensing metabolism in vivo. Acc Chem Res. 21; 42(7):948-57 (2009). Viswanathan S, Kovacs Z, Green K N, Ratnakar S J, Sherry A D. Alternatives to gadolinium-based metal chelates for magnetic resonance imaging. Chem Rev. 12; 110(5):2960-3018 (2010); Aime, S., Delli Castelli, D. & Terreno, E. Highly sensitive MRI chemical exchange saturation transfer agents using liposomes. Angewandte Chemie (International ed 44, 5513-5515 (2005)). Terreno E, Castelli D D, Aime S. Encoding the frequency dependence in MRI contrast media: the emerging class of CEST agents. Contrast Media Mol Imaging. 5(2):78-98 (2010); Terreno E, Castelli D D, Aime S. Challenges for Molecular Magnetic Resonance Imaging, Chem. Rev. 110, 3019-3042 (2010). In addition, several endogenous molecules, including certain protein and peptide fragments (Zhou, J., Lal, B., Wilson, D. A., Laterra, J. & van Zijl, P. C. Amide proton transfer (APT) contrast for imaging of brain tumors. Magn Reson Med 50, 1120-1126 (2003); Zhou, J., Payen, J. F., Wilson, D. A., Traystman, R. J. & van Zijl, P. C. Using the amide proton signals of intracellular proteins and peptides to detect pH effects in MRI. Nat Med 9, 1085-1090 (2003) and U.S. Pat. No. 6,943,033) as well as sugars (U.S. Pat. No. 7,683,617 and van Zijl P C, Jones C K, Ren J, Malloy C R, Sherry A D. MRI detection of glycogen in vivo by using chemical exchange saturation transfer imaging (glycoCEST). Proc Natl Acad Sci USA. 2007 Mar. 13; 104(11):4359-64) and many related compounds (e.g. Ling W, Regatte R R, Navon G, Jerschow A, Assessment of glycosaminoglycan concentration in vivo by chemical exchange-dependent saturation transfer (gagCEST). Proc Natl Acad Sci USA. 19; 105(7): 2266-70 (2008)) can be detected using chemical exchange saturation transfer imaging approaches. There is a large effort for the development of new noninvasive CEST agents for cell labeling and other applications for generating contrast. In addition, several important endogenous substrates and other compounds important for tissue metabolism and function in vivo contain such exchangeable protons, which can be used to diagnose cancer and stroke and potentially other diseases. Currently, radio-frequency (RF) based saturation transfer using either a long low-power RF pulse (Ward, K. M., Aletras, A. H. & Balaban, R. S. A new class of contrast agents for MRI based on proton chemical exchange dependent saturation transfer (CEST). J Magn Reson 143, 79-87 (2000)) or a series of higher power shorter RF pulses (Zhou, J., Lal, B., Wilson, D. A., Laterra, J. & van Zijl, P. C. Amide proton transfer (APT) contrast for imaging of brain tumors. Magn Reson Med 50, 1120-1126 (2003)) is the only available approach to image such CEST compounds. There are several disadvantages for RF saturation, including the need to separately saturate different protons when they occur at different MR frequencies and the need for reference scans to control for the effects of interfering direct water saturation and tissue magnetization transfer effects. Thus, there is a need in the art for improved methods and systems for detecting low concentrations of solute having protons that exchange with water protons.